Biotherapeutics, Molecular Biology Program, Biological Chemistry Program, Cancer Therapeutics, Gene Therapy, Peptide Therapy, Ovarian Cancer, Chronic Myeloid Leukemia
Carol Lim, PhD, is an Associate Professor in the Department of Pharmaceutics and Pharmaceutical Chemistry at the University of Utah and a member of the Cell Response and Regulation Program at Huntsman Cancer Institute. Our lab focuses on developing novel therapies for cancer treatment. Our current targets involve proteins involved in cancer (tumor suppressors or oncogenes). We focus on understanding the molecular mechanisms of signal transduction pathways in cancer, and use peptides or genes as novel therapeutics to disrupt oncogenesis or induce apoptosis.
Targeting of p53 to the Nucleus and Mitochondria for Cancer Therapy The p53 protein plays a pivotal role in suppression of most cancers. Half of all tumors have mutant p53, while inactivity of p53 defines the majority of the remaining cancer cases. Additionally, the apoptotic pathways of p53 have now been clearly delineated. Nuclear accumulation of p53 is essential for its transcriptional activities leading to induction of proteins involved in both the intrinsic and extrinsic apoptotic pathways. Also, p53 triggers a non-transcriptionally mediated intrinsic apoptotic response if delivered to the mitochondria. Indeed, p53 has emerged as a "master switch" for cancer prevention and is being actively pursued as the ultimate cancer therapeutic. We have successfully designed and engineered mitochondrial p53 and nuclear "super p53" as gene therapies for breast cancer, and have tested these new constructs in vitro and in mouse models of triple negative breast cancer. We have evidence that both mitochondrially targeted p53 and nuclear "super p53" can bypass the dominant negative effect in cancers that express mutant p53. The dominant negative effect is one of the major barriers to using p53 as a gene therapy. We are using these new versions of p53 for gene therapy of ovarian cancer in collaboration with Dr. Janat-Amsbury in the School of Medicine.
Chronic Myeloid Leukemia Bcr-Abl is the causative agent of chronic myeloid leukemia (CML). When Bcr-Abl is found in the cytoplasm of cells, it behaves as an oncogene, but if forced to the nucleus, it becomes an apoptotic factor. CML is a myeloproliferative disorder characterized by increased proliferation of granulocytes and their immature precursors. While Gleevec® (imatinib mesylate), a tyrosine kinase inhibitor that binds to the ATP-binding site of Bcr-Abl is regarded as the first line of treatment, about a third of chronic-phase patients treated with Gleevec® develop resistance to it. Resistance in some cases is the result of point mutations in Bcr-Abl which render Gleevec® unable to bind. Our lab exploring alternative strategies to treat CML including the tetramerization motif (coiled-coil domain) as a means to block the activity of Bcr-Abl, and have shown promising results in cells derived from CML patients after viral delivery. Alternative strategies such as these to block Bcr-Abl may prove to be useful therapies for CML, and unlike TKIs, may be refractory to mutational escape by Bcr-Abl. The next stage in our research is translating these novel findings to therapies, and to this end we are using leukemia-specific cell penetrating stapled coiled-coil peptides to treat CML.
Redd Bowman, K.E., P. Lu, E.R. Vander Mause, and C.S. Lim. (2019) Advances in delivery vectors for gene therapy in liver cancer. Ther Deliv. 2019 Dec 16. doi: 10.4155/tde-2019-0076.
Lu, P., K.E. Redd Bowman, S.M. Brown, M.J. Joklik-Mcleod, E.R. Vander Mause, H.T.N. Nguyen, and C.S. Lim (2019) p53-Bad: A Novel Tumor Suppressor-Proapoptotic Factor Hybrid Directed to the Mitochondria for Ovarian Cancer Gene Therapy. Molecular Pharmaceutics, 16(8):3386-98
Lu, P., E.R. Vander Mause, K.E. Redd Bowman, S.M. Brown, L. Ahne, and C.S. Lim (2019) Mitochondrially targeted p53 or DBD subdomain is superior to wild type p53 in ovarian cancer cells even with strong dominant negative mutant p53. J Ovarian Res 12(1):45
Redd Bowman, K.E., J.H. Kim, and C.S. Lim (2019) Narrowing the field: cancer-specific promoters for mitochondrially-targeted p53-BH3 fusion gene therapy in ovarian cancer. J Ovarian Res 12(1):38
Cornillie SP, Bruno BJ, Lim CS, Cheatham TE 3rd (2018) Computational Modeling of Stapled Peptides toward a Treatment Strategy for CML and Broader Implications in the Design of Lengthy Peptide Therapeutics. J Phys Chem B. Apr 12;122(14):3864-3875
Wang Y*, Bruno BJ*, Cornillie S, Nogieira JM, Chen D, Cheatham, TE 3rd, Lim CS, and Chou DH. *Co-first authors. (2017) Application of Thiol-yne/Thiol-ene Reactions for Peptide and Protein Macrocyclizations. Chemistry, 23(29): 7087-7092
- Lu P, Bruno BJ, Rabenau M, Lim CS. (2015) Delivery of drugs and macromolecules to the mitochondria for cancer therapy. Journal of Controlled Release. 2015 Oct 19. pii: S0168-3659(15)30186-3
- Bruno BJ, and Lim CS (2015) Inhibition of Bcr-Abl in human leukemic cells with a coiled-coil protein delivered by a leukemia-specific cell-penetrating peptide. Molecular Pharmaceutics, 12(5):1412-21
- Woessner DW, Eiring AM, Bruno BJ, Zabriskie MS, Reynolds KR, Miller GD, O'Hare T, Deininger MW, and Lim CS (2015) A coiled-coil mimetic intercepts BCR-ABL1 dimerization in native and kinase-mutant chronic myeloid leukemia. Leukemia, 29(8):1668-75
- Okal A., Matissek KJ, Matissek SJ, Price R, Salama M, Janát-Amsbury, MM and Lim CS (2014) Re-engineered p53 Activates Apoptosis In Vivo and Causes Primary Tumor Regression in a Dominant Negative Breast Cancer Xenograft Model. Gene Therapy, 21(10):903-12
- Okal A, Cornillie S, Matissek SJ, Matissek KJ, Cheatham TE 3rd, and Lim CS (2014) Re-Engineered p53 Chimera with Enhanced Homo-Oligomerization That Maintains Tumor Suppressor Activity. Molecular Pharmaceutics, 11(7):2442-52
- Okal A, Mossalam M, Matissek KJ, Dixon AS, Moos PJ, and Lim CS (2013) A chimeric p53 evades mutant p53 transdominant inhibition in cancer cells. Molecular Pharmaceutics, 10(10):3922-33
- Matissek KJ, Okal A, Mossalam M, and Lim CS (2014) Delivery of a monomeric p53 subdomain with mitochondrial targeting signals from pro-apoptotic Bak or Bax. Pharmaceutical Research, 31(9):2503-15
- Matissek KJ, Mossalam M, Okal A, and Lim CS (2013) The DNA binding domain of p53 is sufficient to trigger a potent apoptotic response at the mitochondria. Molecular Pharmaceutics, 10(10):3592-60
- Davis JR, Mossalam M, and Lim CS (2013) Controlled Access of p53 to the Nucleus Regulates Its Proteasomal Degradation by MDM2. Molecular Pharmaceutics, 10(4):1340-9
- Reaz S, Mossalam M, Okal A, and Lim CS (2013) A Single Mutant, A276S of p53, Turns the Switch to Apoptosis. Molecular Pharmaceutics 10(4):1350-9
- Woessner DW and Lim CS (2013) Disrupting BCR-ABL in Combination with Secondary Leukemia-Specific Pathways in CML Cells Leads to Enhanced Apoptosis and Decreased Proliferation, Molecular Pharmaceutics, 10(1): 270–277
- Constance JE, Woessner DW, Matissek KJ, Mossalam M, and Lim CS (2012) Enhanced and Selective Killing of Chronic Myelogenous Leukemia Cells with an Engineered Bcr-Abl Binding Protein and Imatinib, Molecular Pharmaceutics, 9(11):3318-29
- Constance JE and Lim CS (2012) Targeting Malignant Mitochondria with Therapeutic Peptides. Therapeutic Delivery, 3(8): 861-979
- Constance JE, Nishida A, Despres S, and Lim CS (2012) Selective Targeting of c-Abl via a Cryptic Mitochondrial Targeting Signal Activated by Cellular Redox Status in Leukemic and Breast Cancer Cells, Pharmaceutical Research, 9(8):2317-28
- Mossalam M, Matissek KJ (co-first authors), Okal A, Constance JE, and Lim CS (2012) Direct Induction of Apoptosis Using an Optimally Mitochondrially Targeted p53, Molecular Pharmaceutics, 9(5):1449-58
- Dixon AS, Constance JE, Tanaka T, Rabbitts TH, and Lim CS (2012) Changing the Subcellular Location of the oncoprotein Bcr-Abl Using Rationally Designed Capture Motifs, Pharmaceutical Research, 29(4):1098-1109
- Dixon AS, Miller GD (first-coauthors), Bruno BJ, Constance JE, Woessner DW, Fidler TP, Robertson JC, Cheatham TE III, and Lim CS (2012) Improved Coiled-Coil Design Enhances Interaction with Bcr-Abl and Induces Apoptosis, Molecular Pharmaceutics, 9(1):187-195
- Woesser DW, Lim CS, and Deininger MW (2011) Development of an Effective Therapy for CML, The Cancer Journal: The Journal of Principles & Practice of Oncology. Theme issue "Frontiers of Personalized Medicine,” 17(6):477-4
- Dixon AS, Pendley SS, Bruno BJ, Woessner DW, Shimpi AA, Cheatham TE III, and Lim CS (2011) Disruption of Bcr-Abl Coiled-Coil Oligomerization By Design, Journal of Biological Chemistry, 286(31):27751-60